Most solid tumors, including squamous cell carcinoma (SCC) of the oral cavity are now thought to arise through a series of histopathological stages associated with clinical progression. This progression is accompanied by a series of genetic changes which include activation of protooncogenes and loss of somatic chromosomal material associated with inactivation of tumor suppressor genes. We have developed a preliminary progression model for SCC defining several important genetic events involved in the genesis of these tumors. Highly informative microsatellite markers allowed rapid detection of loss of heterozygosity (LOH) in primary tumors and identification of critical suppressor gene loci. A more comprehensible analysis of allelic loss with microsatellite markers and directed fluorescence in situ hybridization (FISH) analysis will now be carried out to identify commonly deleted and amplified oncogene loci. Candidate genes will be tested within critically deleted regions (e.g. p16 on chromosome 9p21) in ongoing parallel studies to determine their direct involvement in the progression of these primary tumors. Knowledge of early and late genetic events will allow establishment of a molecular progression model and will provide the necessary template for the development of novel molecular screening and therapeutic strategies. Thus, the studies outlined in this proposal are aimed at developing a comprehensive genetic model of SCC progression and ultimately new transnational clinical approaches.